Low birth weight (less than 2500 grams) accounts for seven percent of all births in the United States and is the most important factor associated with infant mortality (National Center for Health Statistics, Healthy People 2000: Maternal and Infant Heath Progress Review, 1999).
Chronic lung disease (CLD), also known as bronchopulmonary dysplasia is a frequent and increasing complication in premature infants, usually presenting within the first 4 weeks after birth. The incidence and severity of CLD is inversely proportional to gestational age. Along with respiratory distress syndrome (RDS; also called hyaline membrane disease), it is one of the leading causes of infant mortality in developed countries (National Heart Lung and Blood Institute, NIH Publication No. 98-4081, 1998). CLD is a common complication in premature infants having RDS, although any newborn with severe respiratory problems is at risk for CLD. RDS occurs during the first several hours after birth and is caused by surfactant deficiency. Lack of surfactant leads to alveoli collapse, decreased lung capacity and edema. Premature infants with RDS have difficulty breathing and have an increased oxygen demand, requiring treatment by supplemental oxygen and mechanical ventilation. Lack of surfactant leads to pulmonary inflammation, which is further exacerbated by oxygen toxicity, barotrauma from mechanical ventilation, and infection (Cole, Exp. Opin. Invest. Drugs 9:53, 2000). Though the pathogenesis of CLD is not fully understood, pulmonary inflammation is a common feature in all infants with the disease. The inflammation and injury leads to delayed pulmonary growth and development.
Postnatal treatment with glucocorticoids reduces the inflammation and swelling of airways in ventilator-dependent low birth weight preterm infants, and results in observable clinical changes including increased pulmonary compliance, decreased airway resistance, and accelerated weaning from mechanical ventilation and supplemental oxygen (Cole, supra). Recent reports show that approximately 40% of extremely low birth weight infants receive such treatment (Barrington, BMC Pediatrics 1:1, 2001). This is significant because extremely low birth weight infants account for approximately 1.4% of the 3.5 million babies born in the United States each year (see, e.g., Barrington, supra).
In most species, including man, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (adrenocorticotropin), and are responsive within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety and depression. Cortisol acts by binding to an intracellular, glucocorticoid receptor (GR).
It has been postulated that high levels of cortisol are neurotoxic, particularly in the hippocampus, (see, e.g., Sapolsky et al., Ann. NY Acad Sci. 746:294, 1994; Silva, Annu. Rev. Genet. 31:527, 1997; de Leon et al., J. Clin. Endocrinol & Metab. 82:3251, 1997). Studies of human subjects who have received treatment with exogenous glucocorticoids at therapeutic levels have suggested that glucocorticoids may play a role in short-term, reversible memory impairment. (see, e.g., Wolkowitz et al., Am J. Psychiatry 147:1297, 1990; Keenan et al., Neurology 47:1396, 1996; Newcomer et al., Arch Gen. Psychiatry 56:527-533, 1999).
Thus, despite the success of glucocorticoid therapy for treating pulmonary inflammation in ventilator-dependent low birth weight preterm infants, there are growing concerns regarding the short and long term adverse effects experienced by glucocorticoid treated premature infants. Short term adverse effects may include hyperglycemia, hypertension, hypertrophic obstructive cardiomyopathy, gastrointestinal hemorrhage and perforations, growth failure and hypothalamic-pituitary-adrenal axis suppression (see Shah, et al., Cochrane Database Syst. Rev. 1:CD002058, 2003). The long term neurological disorders are however, the most disconcerting adverse effects. Studies of preterm infants demonstrate that in the long term, there are increased rates of cerebral palsy in those receiving treatment versus those not receiving treatment, and probable increases in rates of total neurodevelopmental disability (Barrington, supra). In rats, glucocorticoid administration in the last days of gestation or first two weeks of postnatal life at doses mimicking pulmonary therapy doses, leads to neurological impairment, including acceleration of differentiation of specific target cells in the central nervous system (see, e.g., Carlos, et al., Teratology 46:45, 1992).
Because of the increasing evidence that glucocorticoid treatment affects neurological development, several experts in the field have urged abandoning glucocorticoid treatment altogether, despite its success in reducing inflammation and accelerating the process of weaning infants off of ventilators (See, e.g., Barrington, supra; Shah, supra; Committee on Fetus and Newborn, Pediatrics 109:330, 2002). Thus, while glucocorticoid therapy is a rapid and effective treatment for inflammation, the potential risk for permanent neurological damage threatens to eliminate this promising treatment.
Fortunately, it has now been discovered that inhibition of glucocorticoid receptor activity in the central nervous system of in ventilator-dependent low birth weight preterm infants by concomitant intrathecal administration of antiglucocorticoids during postnatal glucocorticoid therapy can prevent or reverse neurological damage caused by the postnatal glucocorticoid therapy. Thus, the invention fulfills a need for effective methods to prevent damaging neurological side effects of postnatal glucocorticoid therapy while allowing for the maximum benefit of the postnatal glucocorticoid therapy to be realized.